Stage III colorectal cancer: molecular disparity between primary cancers and lymph node metastases

Colorectal cancers (CRCs) may be classified according to underlying genetic and epigenetic changes including microsatellite instability (MSI) and the CpG island methylator phenotype (CIMP). However the relevance of these molecular characteristics, which are being increasingly used to guide adjuvant therapy, has not been defined for metastatic disease. Since adjunct chemotherapy is designed to prevent or target metastases, molecular characteristics of metastatic disease are relevant. This study evaluates molecular differences between primary colorectal cancers and matched lymph node (LN) metastases.

An Institutional Review Board (IRB)-approved, prospectively maintained, frozen tissue biobank was queried for stage III CRCs previously analyzed for MSI and CIMP. Metastatic cancer-containing LNs from the same patients were retrieved from formalin-fixed paraffin-embedded (FFPE) tissues. DNA was isolated from matched primary tumors and LNs, tested for MSI and CIMP, and the results were compared.

Forty-seven matched LNs from 47 CRC cases were available. Six of 47 primary tumors and 8/47 (17%) LNs were MSI-H (p = 0.25). Thirteen of 47 (28%) primary tumors and 6/47 (13%) LNs were CIMP+ (p < 0.02). Eight patients displayed nine disparities between their primary tumors and LNs: two for MSI and seven for CIMP. Interestingly, of the 13 CIMP+ primary tumors, seven had LN metastases that were CIMP negative.

Molecular characterization, notably the CpG island methylator phenotype, varies between primary tumors and corresponding lymphatic metastases. Although the mechanism for this is unknown, this finding suggests that molecular typing of LNs as well as primary tumors should be considered for molecular-based adjuvant therapy decisions.